Nanoemulsions are composed of nanoscale droplets of one immiscible liquid dispersed within another. Many drugs are hydrophobic, which leads to limited water solubility, causing the delivery of water-insoluble drugs to be a primary focus of drug delivery research. Emulsions provide a central oil core, stably dispersed in water, that can act as a reservoir for hydrophobic drugs. While emulsions have long been used for topical administration, the small size of nanoemulsions makes them potentially attractive for parenteral delivery. In addition to solubilization of hydrophobic drugs, emulsions can reduce pain or irritation upon injection, improve pharmacokinetics, allow for new forms of administration and can provide for sustained or targeted release.
Phospholipid-stabilized soybean oil emulsions were the first approved intravenous emulsion and have been used clinically as i.v. nutritional supplements for over 40 years. Emulsions have also been employed clinically for the delivery of anesthetic, anti-inflammatory and analgesic drugs as well as for blood substitutes. Clinical trials have investigated emulsion formulations for anti-fungal drugs, anti-cancer agents, and radio contrast agents. However, there has not been extensive study of emulsion formulations for the delivery of volatile anesthetics. FIG. 1 provides the chemical structures of several common fluorinated volatile general anesthetics. This class of general anesthetics comprises highly fluorophilic compounds comprising perfluoroethers and substituted perfluoroethers. Fluorine substitution in these compounds provides for use substantially safer than their corresponding hydrocarbon counterparts. Desflurane and sevoflurane, in particular, are the dominant fluorinated volatile anesthetics used in half the general anesthetics supplied in North America. Nanoemulsion delivery systems for anesthetic compounds has promise to enable a new class of intravenously deliverable anesthetic formulations potentially providing a viable alternative to conventional administration of anesthetics via inhalation.
There are many clinical scenarios where the use of intravenous formulations of fluorinated volatile anesthetics offers significant advantages. New applications of intravenous delivery of volatile agents in the modern operating room relate primarily to speed of onset of drug action. When drugs are delivered by inhalation there is an inherent delay in onset, as the concentration in the anesthetic circuit that leads to the patient rises more slowly than at the outflow from the anesthetic vaporizer. The concentration in the lungs rises more slowly still because delivery to the alveoli and transfer to the blood are limited by the rate of ventilation and blood flow. Thus, even with “overpressurization”, in which concentrations higher than the desired equilibrium concentration are delivered transiently, changes in the level of anesthesia are much slower (minutes) than optimal in a rapidly changing clinical environment. This is the primary reason that intravenous agents such as thiopental and propofol are used for “induction” of anesthesia, followed by a transition to inhaled agents as the effects of the intravenous agents dissipate. If it were possible to perform intravenous induction using volatile agents themselves there would be no need to replace one anesthetic with another, thus simplifying the induction process and adding a measure of stability and safety.
There are a number of situations in which rapid changes in the level of anesthesia are required not just for induction of anesthesia and insertion of an endotracheal tube for mechanical ventilation, but also during the middle of surgical procedures. These are typically situations associated with intense but brief stimuli, such as the insertion of “head pins” to stabilize the skull for neurosurgical procedures or direct laryngoscopy for examination of the airway. Deep levels of anesthesia are required to blunt the hemodynamic consequences of these intense stimuli, which are sudden in onset but brief. The ability to rapidly change the level of anesthesia by injecting an agent directly into the bloodstream would prove extremely useful for these and other clinical applications. Further, the brief duration of anesthetic action following a single bolus injection may allow the duration of anesthetic effect to be matched precisely with the duration of the surgical stimulus, thus minimizing hemodynamic consequences and improving safety.
Similarly, during the majority of surgical procedures there is a period of time following intubation of the trachea that the level of surgical stimulation is very low or absent, as the patient is positioned and a sterile field is established. During this time a light plane of anesthesia is required so that blood pressure is maintained. At the time of the surgical incision anesthesia must be deepened quickly. At present this is accomplished by attempting to anticipate the timing of the incision by a minute or two and increasing the level of anesthesia early, so that as the blood pressure falls the incision is made and the blood pressure rises to the desired level. Thus, this is a time of rapid changes in blood pressure and heart rate. One of the major challenges facing the anesthesiologist is maintaining stable hemodynamics in the face of rapidly changing anesthetic requirements at the beginning of a surgical procedure. Again, by more closely matching the onset of anesthetic action with the onset of the surgical stimulus using intravenous anesthetic delivery, stability and safety may be improved substantially.
Beyond the advantages imparted by more rapid titration of drug levels, intravenous delivery has potential to allow or facilitate the use of volatile anesthetics outside of the traditional realm of the operating theater. These include the use of volatile agents for sedation, and for induction and maintenance of general anesthesia under circumstances where delivery via inhalation is difficult or impossible. For example, sedation is occasionally required in the MRI or CT suite, where it is necessary that patients remain still. In addition, sedation is also often required in the clinic for colonoscopy and other uncomfortable procedures. The rapid recovery profile permitted by volatile anesthetics would be ideal in these situations, and significantly more rapid than for the most popular current regimen of fentanyl and midazolam. Further, their ability to blunt responses to noxious stimuli would confer a distinct advantage over propofol, a new intravenous anesthetic that is increasingly used for sedation because of its rapid recovery profile, but that has little or no analgesic property
Recently, substantial research has been directed at developing lipid-based delivery systems for the intravenous administration of fluorinated volatile anesthetics. Warltier et al. and Liu et al. have recently addressed the intravenous administration of halogenated anesthetics via lipid emulsions. (See, Chiari, P. C.; Pagel, P. S.; Tanaka, K.; Krolikowski, J. G.; Ludwig, L. M.; Trillo, R. A.; Puri, N.; Kersten, J. R.; Warltier, D. C. “Intravenous Emulsified Halogenated Anesthetics produce Acute and Delayed Preconditioning against Myocardial Infarction in Rabbits” Anesthesiology 2004, 101, 1160-1166; and Zhou, J.-X.; Luo, N.-F.; Liang, X.-M.; Liu, J. “The Efficacy and Safety of Intravenous Emulsified Isoflurane in Rats” Anesth. Analg. 2006, 102, 129-134). Warltier et al. report that emulsified anesthetics produce acute and delayed preconditioning against myocardial infarction. Liu et al. report that combinations of simple lipids such as soy bean oil and glycerol (Intralipid) could be used for making anesthetic emulsions. While these results demonstrate the potential feasibility of lipid emulsions for the delivery of volatile anesthetics, there are significant drawbacks to this approach which hinder its practical implementation. First, emulsions of volatile fluorinated anesthetics based on Intralipid are not expected to be stable over time at high anesthetic concentrations. The effectiveness of these formulations for intravenous administration of volatile anesthetics, therefore, is expected to degrade significantly as a function of time. This property is undesirable as it renders such lipid-based formulations short practical lifetimes and shelf lives. Second, common lipids such as Intralipid have been shown to emulsify a maximum of 3.6% in volume of sevoflurane. This substantial limitation on the volume of anesthetic capable of emulsification is expected to present a significant challenge for practical implementation of lipid-based delivery systems for intravenously administered fluorinated volatile anesthetics.
An alternative approach to emulsions, which employ micelle systems for the delivery of fluorinated volatile anesthetics, is described in U.S. Patent Publication US2005/0214379 (Mecozzi et al.) published on Sep. 29, 2005. Delivery systems are described comprising fluorinated block copolymers having a hydrophilic block and a fluorinated or semifluorinated block. Applicability of the delivery system for encapsulation and administration of a variety of fluorine containing therapeutic compositions, including sevoflurane, is reported. In this delivery system, fluorinated block copolymers are provided at a concentration larger than the critical micelle concentration so as to form stable supramolecular structures for encapsulating fluorophilic chemical compounds. Specifically, the block copolymers self assemble into micelles wherein the fluorinated or semifluorinated blocks of the copolymer orient toward and surround a fluorous core of the fluorine containing therapeutic. A variety of block copolymer compositions are report as useful for administration of fluorinated therapeutic compositions, include dual block copolymers having a poly(ethylene glycol) block and a perfluorinated alkane block.
It will be appreciated from the foregoing that delivery systems enabling the intravenous administration of fluorinated volatile anesthetics are needed to provide an alternative to vapor inhalation in general anesthesia. Systems and formulations capable of providing highly concentrated emulsions of anesthetic are needed to enable intravenous delivery of anesthetics in amounts required for important clinical applications. Systems and formulations providing concentrated emulsions of anesthetic exhibiting stable particle sizes and anesthetic concentrations are needed to allow practical implementation of intravenous fluorinated volatile anesthetics. Systems and formulations for intravenous delivery of fluorinated volatile anesthetics exhibiting a high degree of biocompatibility and low toxicity are needed.